DOCSLIB.ORG

HACE1-Dependent Protein Degradation Provides Cardiac Protection in Response to Haemodynamic Stress

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
HACE1-Dependent Protein Degradation Provides Cardiac Protection in Response to Haemodynamic Stress ARTICLE Received 18 Sep 2013 | Accepted 11 Feb 2014 | Published 11 Mar 2014 DOI: 10.1038/ncomms4430 OPEN HACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress Liyong Zhang1,2, Xin Chen1,2, Parveen Sharma2, Mark Moon1,2, Alex D. Sheftel1, Fayez Dawood1,2, Mai P. Nghiem2, Jun Wu2, Ren-Ke Li2, Anthony O. Gramolini2,3, Poul H. Sorensen4, Josef M. Penninger5, John H. Brumell6,7,8 & Peter P. Liu1,2,3,7 The HECT E3 ubiquitin ligase HACE1 is a tumour suppressor known to regulate Rac1 activity under stress conditions. HACE1 is increased in the serum of patients with heart failure. Here we show that HACE1 protects the heart under pressure stress by controlling protein degradation. Hace1 deficiency in mice results in accelerated heart failure and increased mortality under haemodynamic stress. Hearts from Hace1 À / À mice display abnormal cardiac hypertrophy, left ventricular dysfunction, accumulation of LC3, p62 and ubiquitinated proteins enriched for cytoskeletal species, indicating impaired autophagy. Our data suggest that HACE1 mediates p62-dependent selective autophagic turnover of ubiquitinated proteins by its ankyrin repeat domain through protein–protein interaction, which is independent of its E3 ligase activity. This would classify HACE1 as a dual-function E3 ligase. Our finding that HACE1 has a protective function in the heart in response to haemodynamic stress suggests that HACE1 may be a potential diagnostic and therapeutic target for heart disease. 1 University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7. 2 Heart and Stroke/Richard Lewar Centre of Excellent for Cardiovascular Research, University of Toronto and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C4. 3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 4 Department of Molecular Oncology, BC Cancer Research Center, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1L3. 5 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr Bohrgasse 3, A-1030 Vienna, Austria. 6 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 7 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 1A8. 8 Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1 Â 8. Correspondence and requests for materials should be addressed to P.P.L. (email: [email protected]). NATURE COMMUNICATIONS | 5:3430 | DOI: 10.1038/ncomms4430 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4430 eart disease is a major cause of death in the developed investigate Hace1’s role in the progression of heart failure, we world, and protection against heart failure is a major subjected Hace1 À / À and Hace1 þ / þ mice to hypertrophic heart Hchallenge1. Animal models have shown that inappropriate failure induced by sTAC20. Sham-operated mice were used as responses of the heart to sustained haemodynamic stress can lead controls. Starting from the second day after surgery, noticeable to heart failure2–4. Protein degradation pathways, including the signs of circulatory failure, including lethargy, impaired mobility, proteasome and autophagy, play a protective role in the response diminished appetite and peripheral oedema were observed in to stress, and their dysregulation appears to underline multiple mice subjected to sTAC. Echocardiographic measurements forms of myocardial disease5–10. In post-mitotic cells such revealed no cardiac physiological functional differences between as cardiomyocytes, turnover of proteins and organelles is Hace1 À / À , Hace1 þ / þ or sham-operated mice at baseline particularly important for cellular protein quality control and (Fig. 1c–e). However, pressure overload induced by sTAC maintenance. Two major pathways within the cell that regulate triggers dramatic decreases in left ventricular (LV) function as proteolysis are the ubiquitin (Ub)–proteasome system (UPS) and measured by echocardiography at days 2 and 4 post operation the autophagy lysosomal pathway6. Whereas the UPS is mainly (Fig. 1c–e). More importantly, these signs of LV dysfunction were involved in the rapid degradation of signalling proteins with more notable in the Hace1 À / À sTAC-treated mice as shown by a short half-lives, autophagy can selectively remove more significantly decreased percentage of LV fractional shortening persistent protein aggregates and damaged organelles5. Both and severely dilated LV, which was indicated by a significant proteasome-mediated degradation and selective autophagy increase in both LV end-diastolic dimension and LV end-systolic require ubiquitination of the cargo, which is then recognized by dimension compared with wild-type (WT) mice with the same Ub receptors directing it to either 26S proteasomes or lysosome treatment (Fig. 1c–e). Moreover, The LV dysfunction resulted in for degradation6. HACE1, as a novel stress inducible Ub E3 significantly higher mortality rates in Hace1 À / À mice following protein ligase, has potential roles in both proteolytic systems. sTAC; 40% (8/20) of Hace1 À / À mice died between day 1 and day We and others previously reported that HACE1 is involved 4 post sTAC, compared with only 16% (3/19) of the Hace1 þ / þ in proteasome-mediated protein degradation11–17. However, mice (log-rank w2-test, Po0.001; Fig. 1f). This was accompanied HACE1’s involvement in autophagy-mediated protein degra- by a significant increase in cardiac mass as measured by growing dation has never been explored. heart weight/body weight ratio in Hace1 À / À sTAC mice Increases in autophagic flux have been documented in virtually compared with Hace1 þ / þ sTAC mice (Fig. 1g). An increase in all forms of human cardiovascular disease, including ventricular myocyte cross-sectional area, as revealed by haematoxylin and hypertrophy and heart failure18,19. This is indicative of a eosin staining of left ventricle cross-sections, confirmed that the requirement for autophagy in the maintenance of cellular increase in heart weight/body weight ratio in Hace1 À / À sTAC homoeostasis during ventricular hypertrophic remodelling. mice was caused by myocyte enlargement (Fig. 1i). Consistent Although HACE1 is highly expressed in the heart, nothing is with severe heart failure, Hace1 À / À sTAC mice also had a known about its function in the heart. The emerging role of other significantly higher lung weight/body weight ratio, accompanied E3 ligase and Ub-binding proteins in selective autophagy suggests by pulmonary oedema, compared with Hace1 þ / þ sTAC mice that HACE1 may also participate in this process. (Fig. 1h). Expression of atrial natriuretic peptide precursor A, a Here we demonstrate for the first time that HACE1 is essential biomarker of cardiac stress and hypertrophy21–23, was also for the completion of selective autophagic flux. Hace1 deficiency elevated in Hace1 À / À sTAC hearts (Fig. 1j). In addition, in our results in increased accumulation of ubiquitinated protein initial pilot studies of HACE1 protein level changes in human aggregates in stressed myocardium due to impaired autophagy clinical plasma samples with heart failure, we also observed some and thus accelerates cardiac dysfunction. degree of correlation between HACE1 and B-type natriuretic peptide (Supplementary Fig. 1). However, the data only explain 2 Results 19.5% of the relationship (as per R value), and thus HACE1 and HACE1 is upregulated in human heart failure. To clarify the B-type natriuretic peptide do ultimately reflect different biological processes. These findings indicate that, in the absence of Hace1, role of HACE1 in the development of heart failure, we performed in silico GEO profiles’ analysis of HACE1 gene expression related to haemodynamic stress induced by sTAC triggers rapid decompensated cardiac hypertrophic remodelling, progressing human heart disease. Our search indicated that HACE1 gene expression is upregulated in dilated cardiomyopathy (DCM) to heart failure and increased mortality in these mice. compared with non-failing hearts (GEO accession code GDS2206). Accumulation of protein aggregates in Hace1 À / À sTAC To confirm this, we examined HACE1 messenger RNA expression myocardium. To explore Hace1’s role in controlling cardiac in a panel of heart tissue biopsies from heart failure patients as well as non-failing heart controls. Significantly, increased HACE1 gene remodelling at the cellular level, LV sections of sTAC mice were subjected to transmission electron microscopy (TEM) examination. expression was detected in cardiac tissues of heart failure patients À / À compared with non-failing hearts; there was a 2.5-fold increase in Ultrastructural analysis of Hace1 sTAC hearts showed a dis- organized sarcomere structure and significantly more structures HACE1 gene expression in ischaemic cardiomyopathy and more than a 3-fold increase in DCM (Fig. 1a). In addition, markedly resembling autophagic vacuoles (Supplementary Fig. 2a). It is noteworthy that these cellular phenotypes are similar to those elevated Hace1 gene expression was detected in a murine model of heart failure induced by severe transverse aortic constriction previously observed in Atg5-deficient hearts, which are defective in protein/organelle turnover via autophagy5. We also observed fewer (sTAC) compared with a sham-operated control group at 4 days À / À post operation (unpaired
Load more

Recommended publications
  • Meqtl and Ncrna Functional Analyses of 102 GWAS-Snps Associated with Depression Implicate HACE1 and SHANK2 Genes Diana M
    Ciuculete et al. Clinical Epigenetics (2020) 12:99 https://doi.org/10.1186/s13148-020-00884-8 RESEARCH Open Access meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes Diana M. Ciuculete1* , Sarah Voisin2, Lara Kular3, Jörgen Jonsson1, Mathias Rask-Andersen4, Jessica Mwinyi1 and Helgi B. Schiöth1,5 Abstract Background: Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results: We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (total n = 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (padj. < 0.05) with meQTL effect. Lower DNAm at cg02098413 located in the HACE1 promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (praw = 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated with HACE1 mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lower HACE1 mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p = 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2)(padj.
    [Show full text]
  • The Uvomorulin-Anchorage Protein a Catenin Is a Vinculin
    Proc. Nail. Acad. Sci. USA Vol. 88, pp. 9156-9160, October 1991 Cell Biology The uvomorulin-anchorage protein a catenin is a vinculin homologue KURT HERRENKNECHT*, MASAYUKI OZAWA*t, CHRISTOPH ECKERSKORN*, FRIEDRICH LOTTSPEICHt, MARTIN LENTER*, AND ROLF KEMLER*§ *Max-Planck-Institut ffir Immunbiologie, FG Molekulare Embryologie, D-7800 Freiburg, Federal Republic of Germany; and tMax-Planck-Institut ffr Biochemie, D-8033 Martinsried, Federal Republic of Germany Communicated by Franqois Jacob, July 18, 1991 (receivedfor review June 25, 1991) ABSTRACT The cytoplasmic region of the Ca2+- domain is well conserved in other cadherins, it is possible that dependent cell-adhesion molecule (CAM) uvomorulin associ- catenins may also complex with other members of this gene ates with distinct cytoplasmic proteins with molecular masses family (13, 14). Here we have produced antibodies against a of 102, 88, and 80 kDa termed a, (3, and ycatenin, respectively. catenin and show that a catenin is indeed associated with This complex formation links uvomorulin to the actin filament cadherins from human, mouse, and Xenopus. We have network, which seems to be of primary importance for its cloned and sequenced¶ the cDNA coding for a catenin and cell-adhesion properties. We show here that antibodies against have established the primary protein structure. Sequence a catenin also immunoprecipitate complexes that contain hu- comparison reveals homology to vinculin, a well-known man N-cadherin, mouse P-cadherin, chicken A-CAM (adhe- adherens-type and focal contact protein. rens junction-specific CAM; also called N-cadherin) or Xeno- pus U-cadherin, demonstrating that a catenin is complexed with other cadherins.
    [Show full text]
  • 1 Supporting Information for a Microrna Network Regulates
    Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia.
    [Show full text]
  • Mir-15A and Mir-16-1 Cluster Functions in Human Leukemia
    MiR-15a and miR-16-1 cluster functions in human leukemia George A. Calin*†‡, Amelia Cimmino*§, Muller Fabbri*, Manuela Ferracin¶, Sylwia E. Wojcik*, Masayoshi Shimizu*§, Cristian Taccioli*, Nicola Zanesi*, Ramiro Garzon*, Rami I. Aqeilan*, Hansjuerg Alder*, Stefano Volinia*ʈ, Laura Rassenti**, Xiuping Liu*, Chang-gong Liu*, Thomas J. Kipps**, Massimo Negrini¶, and Carlo M. Croce*†† *Human Cancer Genetics Program and †Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210; §Department of Biochemistry and Biophysics ‘‘F. Cedrangolo,’’ Medical School, Second University of Naples, 80138 Naples, Italy; ¶Department of Experimental and Diagnostic Medicine, Interdepartment Center for Cancer Research and ʈMorphology and Embryology Department, University of Ferrara, 44100 Ferrara, Italy; and **Department of Medicine, University of California at San Diego, La Jolla, CA 92093 Contributed by Carlo M. Croce, January 16, 2008 (sent for review December 6, 2007) MicroRNAs (miRNAs) are short noncoding RNAs regulating gene megakaryocytic leukemia (22). These data support a role for expression that play roles in human diseases, including cancer. Each miR-15a and miR-16-1 as tumor-suppressor genes (TSGs) in CLLs miRNA is predicted to regulate hundreds of transcripts, but only few and perhaps in other malignancies in which these genes are lost or have experimental validation. In chronic lymphocytic leukemia (CLL), down-regulated. the most common adult human leukemia, miR-15a and miR-16-1 are Here, to investigate the mechanism of action of miR-15a and lost or down-regulated in the majority of cases. After our previous miR-16-1 as tumor suppressors in leukemias, we analyzed the work indicating a tumor suppressor function of miR-15a/16-1 by effects of miR-15a and miR-16-1 on transcriptome and proteome in targeting the BCL2 oncogene, here, we produced a high-throughput MEG-01 leukemic cells.
    [Show full text]
  • Kif1b Rab7a Lmna
    Title: Charcot-Marie-Tooth Neuropathy Type 2 GeneReview Molecular Genetics: Less Commonly Involved Genes Author: Bird TD Updated: March 2016 KIF1B Gene structure. KIF1B comprises 47 exons and 167.13 kb of DNA. Pathogenic allelic variants. See Table A, Locus Specific and HGMD Normal gene product. Kinesin-like protein KIF1B is involved in axonal transport of synaptic vesicle precursors [Zhao et al 2001]. The kinesin superfamily of proteins is essential for intracellular transport along microtubules. Abnormal gene product. There may be a defect in the transport of synaptic vesicles. RAB7A Gene structure. RAB7A has six exons and 87.9 kb of DNA. Pathogenic allelic variants. See Table A. Normal gene product. Ras-related protein Rab-7a belongs to the RAB family of Ras- related GTPases essential for the regulation of intracellular membrane trafficking. Rab- 7a is involved in transport between late endosomes and lysosomes. RAB-interacting lysosomal protein (RILP) induces the recruitment of dynein-dynactin motors and regulates transport toward the minus-end of microtubules [Verhoeven et al 2003]. Abnormal gene product. Abnormal Rab-7a may cause malfunction of lysosomes and inhibit neurite outgrowth [Spinosa et al 2008, Bucci & Deluca 2012]. LMNA Gene structure. LMNA has 12 exons spread over 24 kb of genomic DNA. Pathogenic allelic variants. The most common pathogenic variant found in individuals with CMT2B1 is p.Arg298Cys, a founder mutation in North Africa [Bouhouche et al 2007, De Sandre-Giovannoli et al 2002]. See also Table A. Table 5. Selected LMNA Variants DNA Nucleotide Protein Amino Acid Class of Variant Allele Reference Sequences Change Change Benign c.1908C>T p.= 1 c.398G>T p.Arg133Leu NM_170707.2 c.892C>T p.Arg298Cys Pathogenic NP_733821.1 c.1411C>T p.Arg471Cys c.1579C>T p.Arg527Cys Note on variant classification: Variants listed in the table have been provided by the author.
    [Show full text]
  • The Genetics of Bipolar Disorder
    Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF.
    [Show full text]
  • Medical Cell Biology Microfilaments 1 Thomas J
    MEDICAL CELL BIOLOGY MICROFILAMENTS September 24, 2003 Thomas J. Schmidt, Ph.D. Department of Physiology and Biophysics 5-610 BSB, 335-7847 Reading Assignment: Molecular Biology of the Cell (4th ed..), 2001, by B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter; Chapter 16, pp. 907-925, 927-939, 943-981 Key Concepts: 1. The cytoskeleton is a complex network of protein filaments (actin filaments, intermediate filaments and microtubules) that traverses the cell cytoplasm and performs many important and diverse cellular functions. 2. Thin actin filaments, which are present in all cells, are composed of two helically interwined chains of G-actin monomers. 3. A variety of proteins including spectrin, filamin, gelsolin, thymosin, profilin, fimbrin and α-actinin regulate the dynamic state of actin filaments 4. The spectrin membrane skeleton, which is composed primarily of actin filaments located at the cytoplasmic surface of the cell membrane, is essential for maintaining cellular shape and elasticity as well as membrane stability. 5. Cell motility is mediated by actin-filaments organized into specific cellular projections referred to as lamellipodia and filopodia. Medical Cell Biology Microfilaments 1 Thomas J. Schmidt, Ph.D. Email: [email protected] September 24, 2003 Key Terms: cytoskeleton cytochalasins actin filaments (actin) phalloidins intermediate filaments (vimentin, spectrin membrane skeleton lamin) spectrin microtubules (tubulin) actin microfilaments ankyrin F-actin band 4.1 G-actin glycophorin myosin II band 3.0 myosin I hereditary spherocytosis actin microfilaments hereditary elliptocytosis treadmilling sickle cell anemia actin-binding proteins spectrin supergene family spectrin spectrin filamin α-actin fimbrin dystrophin α-actinin microvilli gelsolin terminal web thymosin lamellipodium profilin filopodia villin stress fibers contractile bundles Medical Cell Biology Microfilaments 2 Thomas J.
    [Show full text]
  • Changes in Adhesion Complexes Define Stages in the Differentiation
    Changes in Adhesion Complexes Define Stages in the Differentiation of Lens Fiber Cells David C. Beebe, Oleg Vasiliev, Jianli Guo, Ying-Bo Shui, and Steven Bassnett PURPOSE. During their differentiation, lens fiber cells elongate, he lens is composed of epithelial cells at various stages of detach from the lens capsule, associate at the sutures, and Tdifferentiation (Fig. 1A, 1B). The surface of the lens nearest degrade all cytoplasmic membrane-bound organelles. Changes the cornea is covered by a simple cuboidal epithelium. In the in the expression or organization of cell adhesion and cyto- avian lens, the epithelium thickens at the lens periphery, form- skeleton-associated proteins were correlated with these events ing the annular pad. Mitosis at the border of the epithelium and during fiber cell differentiation in chicken embryos. the annular pad produces cells that will eventually differentiate into the fiber cells that comprise the bulk of the lens. During METHODS. Fixed or living lenses were sliced with a tissue slicer, their differentiation, fiber cells become progressively longer permeabilized or extracted with detergents, stained with anti- until their tips reach the sutures at the anterior and posterior bodies or fluorescent-labeled phalloidin, and viewed with a poles of the lens. At the sutures, they contact fiber cells from confocal microscope. The distribution of N-cadherin in elon- the opposite side of the lens (Fig. 1B). Shortly after reaching gating and mature fiber cells was determined by Western blot the sutures, fiber cells detach from the lens capsule and are analysis. Reverse transcription–polymerase chain reaction (RT- covered by the next cohort of differentiating cells.1 Fiber cells PCR) was used to determine the distribution of vinculin and deeper in the lens abruptly degrade their nuclei, endoplasmic paxillin transcripts.
    [Show full text]
  • In Silico Prediction and Experimental Validation of Natural Antisense Transcripts in Two Cancer-Associated Regions of Human Chromosome 6
    1099-1108 27/2/2009 01:48 ÌÌ ™ÂÏ›‰·1099 INTERNATIONAL JOURNAL OF ONCOLOGY 34: 1099-1108, 2009 In silico prediction and experimental validation of natural antisense transcripts in two cancer-associated regions of human chromosome 6 LAURA MONTI1*, RAFFAELLA CINQUETTI1*, ALESSANDRO GUFFANTI2*, FRANCESCO NICASSIO3, MATTIA CREMONA4, GIOVANNI LAVORGNA5, FABRIZIO BIANCHI3, FRANCESCA VIGNATI1, DAVIDE CITTARO6, ROBERTO TARAMELLI1 and FRANCESCO ACQUATI1 1Department of Biotechnology and Molecular Sciences, University of Insubria, Via JH Dunant 3, I-21100 Varese; 2Nanotechnologies Group, Institute of Biomedical Technologies, CNR, Via Fantoli 16/15, I-20138 Milano; 3IFOM - FIRC Institute of Molecular Oncology, Via Adamello 16, I-20139 Milano; 4Proteomic Unit, Department of Experimental Oncology, National Institute of Cancer, Via Venezian 21, I-20133 Milano; 5DIBIT, San Raffaele Hospital, Via Olgettina 58, I-20132 Milano; 6HPC and Bioinformatics Systems @ Informatics Core, FIRC Insitute of Molecular Oncology (IFOM), Via Adamello 16, I-20139 Milano, Italy Received August 28, 2008; Accepted October 27, 2008 DOI: 10.3892/ijo_00000237 Abstract. Antisense transcription has long been recognized human malignancies, such as non-Hodgkin's lymphomas, as a mechanism involved in the regulation of gene expression. melanoma and carcinomas of the mammary gland, ovary, Therefore, several human diseases associated with abnormal uterus, stomach, kidney and salivary gland (1-3). The involve- patterns of gene expression might display antisense RNA- ment of this chromosome in the pathogenesis of the above- mediated pathogenetic mechanisms. Such issue could be mentioned cancer types has been demonstrated by LOH particularly relevant for cancer pathogenesis, since deregulated studies and chromosome-transfer assays, which led to the gene expression has long been established as a hallmark of identification of several regions of minimal deletion spanning cancer cells.
    [Show full text]
  • Snapshot: Nonmotor Proteins in Spindle Assembly Amity L
    SnapShot: Nonmotor Proteins in Spindle Assembly Amity L. Manning and Duane A. Compton Department of Biochemistry, Dartmouth Medical School, Hanover, NH and Norris Cotton Cancer Center, Lebanon, NH 03755, USA Protein Name Species Localization Function in Spindle Assembly DGT/augmin complex Human, fl y Spindle microtubules Boosts microtubule number by regulating γ-tubulin NuSAP Human, mouse, frog Central spindle Nucleation, stabilization, and bundling of microtubules near chromo- somes *RHAMM/HMMR Human, mouse, frog (XRHAMM) Centrosomes, spindle poles, spindle Nucleates and stabilizes microtubules at spindle poles; infl uences cyclin midbody B1 activity *TACC 1-3 Human, mouse, fl y (D-TACC), worm (TAC-1), Centrosomes, spindle poles Promotes microtubule nucleation and stabilization at spindle poles frog (Maskin), Sp (Alp7) Stabilization *TOGp Human, mouse, fl y (Minispindles/Msps), Centrosomes, spindle poles Promotes centrosome and spindle pole stability; promotes plus-end worm (ZYG-9), frog (XMAP215/Dis1), Sc microtubule dynamics Microtubule Nucleation/ Microtubule (Stu2), Sp (Dis1/Alp14) Astrin Human, mouse (Spag5) Spindle poles, kinetochores Crosslinks and stabilizes microtubules at spindle poles and kinetochores; stabilizes cohesin *HURP/DLG7 Human, mouse, fl y, worm, frog, Sc Kinetochore fi bers, most intense near Stabilizes kinetochore fi ber; infl uences chromosome alignment kinetochores *NuMA Human, mouse, fl y (Mud/Asp1), frog Spindle poles Formation/maintenance of spindle poles; inhibits APC/C at spindle poles *Prc1 Human, mouse,
    [Show full text]
  • Titin N2A Domain and Its Interactions at the Sarcomere
    International Journal of Molecular Sciences Review Titin N2A Domain and Its Interactions at the Sarcomere Adeleye O. Adewale and Young-Hoon Ahn * Department of Chemistry, Wayne State University, Detroit, MI 48202, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-(313)-577-1384 Abstract: Titin is a giant protein in the sarcomere that plays an essential role in muscle contraction with actin and myosin filaments. However, its utility goes beyond mechanical functions, extending to versatile and complex roles in sarcomere organization and maintenance, passive force, mechanosens- ing, and signaling. Titin’s multiple functions are in part attributed to its large size and modular structures that interact with a myriad of protein partners. Among titin’s domains, the N2A element is one of titin’s unique segments that contributes to titin’s functions in compliance, contraction, structural stability, and signaling via protein–protein interactions with actin filament, chaperones, stress-sensing proteins, and proteases. Considering the significance of N2A, this review highlights structural conformations of N2A, its predisposition for protein–protein interactions, and its multiple interacting protein partners that allow the modulation of titin’s biological effects. Lastly, the nature of N2A for interactions with chaperones and proteases is included, presenting it as an important node that impacts titin’s structural and functional integrity. Keywords: titin; N2A domain; protein–protein interaction 1. Introduction Citation: Adewale, A.O.; Ahn, Y.-H. The complexity of striated muscle is defined by the intricate organization of its com- Titin N2A Domain and Its ponents [1]. The involuntary cardiac and voluntary skeletal muscles are the primary types Interactions at the Sarcomere.
    [Show full text]
  • Download Ppis for Each Single Seed, Thus Obtaining Each Seed’S Interactome (Ferrari Et Al., 2018)
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.14.425874; this version posted January 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias Nikoleta Vavouraki1,2, James E. Tomkins1, Eleanna Kara3, Henry Houlden3, John Hardy4, Marcus J. Tindall2,5, Patrick A. Lewis1,4,6, Claudia Manzoni1,7* Author Affiliations 1: Department of Pharmacy, University of Reading, Reading, RG6 6AH, United Kingdom 2: Department of Mathematics and Statistics, University of Reading, Reading, RG6 6AH, United Kingdom 3: Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom 4: Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom 5: Institute of Cardiovascular and Metabolic Research, University of Reading, Reading, RG6 6AS, United Kingdom 6: Department of Comparative Biomedical Sciences, Royal Veterinary College, London, NW1 0TU, United Kingdom 7: School of Pharmacy, University College London, London, WC1N 1AX, United Kingdom *Corresponding author: [email protected] Abstract The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein- protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes.
    [Show full text]